Huntington's disease (HD) is devastating hereditary neurodegenerative disorder characterized by a severe movement disorder, mood and emotional disturbances, and cognitive decline before premature death. It is caused by a CAG repeat expansion in the gene encoding huntingtin (htt), but the mechanism whereby mutant htt (mhtt) ultimately induces selective neurodegeneration is still unknown. There is substantial evidence from multiple HD models that mhtt induces apoptotic cell death processes and mitochondrial dysfunction. XIAP is a potent inhibitor of apoptosis and thus represents an attractive target for neuroprotection in Huntington's disease. The goal of this proposal is to determine the potential therapeutic utility of a novel gene delivery approach, using an AAV-vector approach to deliver the gene encoding XIAP to the major site of neurodegeneration in Huntington's disease, the neostriatum. The proposed experiments in genetic mouse models of Huntington's disease arise from the observations that (i) we have found that XIAP has neuroprotective actions against mhtt- induced toxicity in vitro, (ii) that this effect is potentially mediated by inhibitory actions against Smac/DIABLO or Omi, rather than caspase inhibition, (iii) that our adeno-associated viral (AAV) vector delivery system results in widespread gene expression within the striatum, and (iv) pilot experiments suggest that XIAP gene delivery improves phenotype in a mouse model of Huntington's disease. Specifically, we will examine whether an AAV gene therapy approach to deliver the anti-apoptotic agent XIAP to striatal neurons improves outcome and reduces neurodegeneration in animal models of Huntington's disease, by examining AAV-dXIAP's effects in the N171-82Q "fragment" mouse model of Huntington's disease, and in a second "full length" HD model, YAC-128 HD mice. We will also elucidate whether XIAP'S neuroprotective anti-apoptotic actions are due to inhibition of Smac/DIABLO or Omi/HtrA2, rather than direct effects on caspases in HD mice. We will generate AAV vectors carrying dXlAP with point mutations either disabling its ability to bind to Smac/DIABLO-Omi, or caspases, and examine their effects on HD pathobiology in an HD mouse model. The outcomes of these studies will provide a substantial foundation for larger studies to determine cell damage pathways underlying HD pathogenesis, and to develop an effective gene-delivery approach for the treatment of Huntington's disease. [unreadable] [unreadable] [unreadable]